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Academic Commons Search Resultsen-usGenome-Wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish populationhttps://academiccommons.columbia.edu/catalog/ac:183129
Liu, Xinmin; Cheng, Rong; Verbitsky, Miguel; Kisselev, Sergey; Browne, Andrew; Mejia-Santana, Helen; Louis, Elan D.; Cote, Lucien J.; Andrews, Howard F.; Waters, Cheryl H.; Ford, Blair; Frucht, Steven; Fahn, Stanley; Marder, Karen; Clark, Lorraine N.; Lee, Joseph H.http://dx.doi.org/10.7916/D86971ZMMon, 08 Sep 2014 22:59:39 +0000To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified. We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls. We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 × 10-5). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 × 10-4), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 × 10-4) and GBA (Chr1q21; rs2990245, p = 0.015). We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway.Genetics, Neurosciencesxl2269, rc2116, mmv2003, sk3030, hm28, edl2, lc24, hfa1, cw345, bf25, sf1, ksm1, lc654, jhl2Pathology and Cell Biology, Taub Institute, Medicine, Columbia Genome Center, Sergievsky Center, Epidemiology, Neurology, BiostatisticsArticlesCase-control study of the parkin gene in early-onset Parkinson diseasehttps://academiccommons.columbia.edu/catalog/ac:130035
Clark, Lorraine N.; Afridi, Shehla; Karlins, Eric; Wang, Yuanjia; Mejia-Santana, Helen; Harris, Juliette; Louis, Elan D.; Cote, Lucien J.; Andrews, Howard F.; Fahn, Stanley; Waters, Cheryl H.; Ford, Blair; Frucht, Steven; Ottman, Ruth; Marder, Karenhttp://hdl.handle.net/10022/AC:P:9930Thu, 10 Mar 2011 11:25:24 +0000Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD.Neuroscienceslc654, yw2016, hm28, edl2, lc24, hfa1, sf1, cw345, bf25, sf216, ro6, ksm1Pathology and Cell Biology, Taub Institute, Sergievsky Center, Biostatistics, Neurology, Center for Parkinson's Disease and Other Movement Disorders, EpidemiologyArticlesMotor phenotype of LRRK2 G2019S carriers in early-onset Parkinson diseasehttps://academiccommons.columbia.edu/catalog/ac:130030
Alcalay, Roy Nissim; Mejia-Santana, Helen; Tang, Ming Xin; Rosado, Llency E.; Verbitsky, Miguel; Kisselev, Sergey; Ross, Barbara M.; Louis, Elan D.; Comella, Cynthia L.; Colcher, Amy; Jennings, Danna; Nance, Martha A.; Bressman, Susan; Scott, William K.; Tanner, Caroline; Mickel, Susan F.; Andrews, Howard F.; Waters, Cheryl H.; Fahn, Stanley; Cote, Lucien J.; Frucht, Steven; Ford, Blair; Rezak, Michael; Novak, Kevin; Friedman, Joseph H.; Pfeiffer, Ronald; Marsh, Laura; Hiner, Bradley; Siderowf, Andrew; Van Vliet, Elise A.; Ottman, Ruth; Clark, Lorraine N.; Marder, Karenhttp://hdl.handle.net/10022/AC:P:9929Thu, 10 Mar 2011 10:01:55 +0000Objective: To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design: Cross-sectional observational study. Setting: Thirteen movement disorders centers. Participants: Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures: LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results: Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). Conclusion: Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course.Neurosciencesrna2104, hm28, mxt1, lr2244, mmv2003, sk3030, edl2, hfa1, cw345, sf1, lc24, sf216, bf25, ec668, ro6, lc654, ksm1Center for Parkinson's Disease and Other Movement Disorders, Sergievsky Center, Biostatistics, Pathology and Cell Biology, Taub Institute, Epidemiology, NeurologyArticlesRisk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort methodhttps://academiccommons.columbia.edu/catalog/ac:129851
Wang, Yuanjia; Clark, Lorraine N.; Louis, Elan D.; Mejia-Santana, Helen; Harris, Juliette; Cote, Lucien J.; Waters, Cheryl H.; Andrews, Howard F.; Ford, Blair; Frucht, Steven; Fahn, Stanley; Ottman, Ruth; Rabinowitz, Daniel; Marder, Karenhttp://hdl.handle.net/10022/AC:P:9887Thu, 03 Mar 2011 11:45:36 +0000Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis.Neurosciencesyw2016, lc654, edl2, hm28, lc24, cw345, hfa1, bf25, sf216, sf1, ro6, dr105, ksm1Biostatistics, Pathology and Cell Biology, Center for Parkinson's Disease and Other Movement Disorders, Epidemiology, Sergievsky Center, Neurology, StatisticsArticles